The role of (novel) candidate genes in plasma and hepatic lipoprotein metabolism and their associations with atherosclerotic cardiovascular and fatty liver disease

In a search for novel insight in lipid and lipoprotein metabolism, we have previously sequenced numerous candidate genes (Agilent SureSelect platform; 800x) in Lifelines participants with extreme dyslipidemia. In short, we have selected apparently healthy women and men (ages 20-45) using an age-block design with low-density lipoprotein (LDL) cholesterol below the first percentile, normal LDL cholesterol (45-55th percentile) and LDL cholesterol above the 99th percentile. In these studies, we have identified carriers of loss of function and gain of function variants in canonical genes while others were shown to suffer from polygenic forms of hypo- or hypercholesterolemia (PMID: 29459468). In the majority of cases, however, we have so far been unable to assign the genetic etiology of their extreme dyslipidemia. On the other hand, rare variants (frequency ˂ 0.1%) in numerous promising candidate genes were identified, and we would like to study some of these genes in greater depth. Haplotypes of family members can for example help to find additional family members and to carry out segregation analyses using identity by decent analyses.
In addition, multiple novel lipid candidate genes have been proposed through recent GWAS as well as experimental mouse studies, and we would like to study the possible involvement of these genes in (lipid) metabolism in Lifelines as a whole. Such studies may help us replicate findings from e.g. the UKBiobank.
Finally, we are studying novel candidate genes in the lab for which we have found evidence that they affect plasma and hepatic lipids in mice. Studies in Lifelines can help us translate our findings to humans and vice versa.